The treatment of constipation problems has been a concern of physicians for years. Constipation has been defined as less than one bowel movement per week. Other components of constipation include difficulties with defecation and stool hardness.
Alternating constipation and diarrhea or painful constipation are symptoms of one of the most common ailments in medicine and in the practice of gastroenterology--the irritable bowel syndrome. In this syndrome, the constipation is believed to be due to altered colonic motility, but neural and hormonal abnormalities and psychosocial stresses may also contribute to the syndrome.
Other common and accepted causes of constipation include: endocrine disorders such as diabetes, hypothyroidism, and hyper/hypocalcemia; spinal and head injuries which disrupt the parasympathetic nerve circuits to the colon; anal canal or rectal contraction abnormalities; pelvic floor abnormalities preventing proper angulation for defecation; neuromuscular disorders such as intestinal pseudo-obstruction and colonic inertia. Encopresis is a constipation problem in pediatrics. Constipation also is a major concern of the elderly populations who are sedentary, who may have inadequate diets, and who take numerous medications which may interfere with normal bowel function.
Treatment of common and typical constipation takes the form of time honored remedies ranging from mineral oil to castor oil to fiber and bran. Treatments have been empirical because the mechanisms and causes of constipation are still poorly understood.
The four major classes of laxatives which can be used in the treatment of constipation are: osmotic laxatives, bulking agents, stimulant agents, and stool softeners. The osmotic laxatives are saline cathartics and include compounds such as lactulose, golytely or colyte, mannitol or mannose, or magnesium citrate. Lactulose is available as a component of the commercial product Chronulac, a non-absorbable synthetic disaccharide (lactulose, 10 g; plus galactose, 2.2 g; and lactose 1.2 g per dose).
Chronulac is poorly absorbed and reaches the colon virtually unchanged where it is broken down by colonic bacteria to volatile fatty acids. Production of these fatty acids results in a slight acidification in the intestine and results in increased osmotic pressure. In turn, this causes an increase in stool water content and stool softening.
Chronulac often takes 24-28 hours to work. Three percent of a dose generally appears in the urine. A major side effect is excessive gas. Chronulac is available by prescription and only in a syrup form. Usual doses are 30-40 gm three to four times a day.
Golytely and colyte are balanced electrolyte solutions plus polyethylene glycol. Their primary use is to prepare the colon for barium enema studies and for colonoscopy. Polyethylene glycol is not absorbed and causes an osmotic diarrhea. The electrolytes are absorbed to maintain the body's fluid balance during intense laxation. These solutions are advantageous in that the colon is thoroughly cleansed and no explosive gases are produced, which would become problematic if polypectomy is planned. The major disadvantage is that patients must drink 4 liters of the solution in 3-4 hours and many patients are unable to do so or find this very unpleasant because of bloating and nausea.
Mannitol or mannose agents are poorly absorbed carbohydrates, but are seldom used because enough carbohydrate does get absorbed to present an osmotic load to the kidney resulting in diuresis. Gas formation makes polypectomy dangerous. Magnesium citrate is a lemon-lime flavored liquid which is an effective laxative when more vigorous laxation is needed.
Bulking agents include fiber products (such as Metamucil) and Perdiem. Increases in stool weight, stimulation of colonic motility and increases in stool water have been described after using these agents. Bulking agents are the preferred products used by most gastroenterologists for common constipation or for the constipation associated with the irritable bowel syndrome. However, almost all patients complain of the mucilagenous consistency of metamucil-type preparations. Many new products have been developed to cover-up the fiber nature of these preparations but none have been particularly successful. The product is also unsatisfactory for patients with esophageal or gastric motility disorders. These patients have trouble swallowing and experience bloating, distention and increased gas after ingestion.
Perdiem is an effective product since it provides the bran psyllium in a well-tolerated granular form. However, administration of Perdiem is unusual in that the crystals (one teaspoon) are supposed to be swallowed dry. Perdiem can also be used with senna. The senna adds a laxative to the fiber for the patient with more severe constipation.
Stimulant agents include phenolphthalein-containing laxatives, castor oil and Dulcolax. Phenolphthalein-containing laxatives, e.g., Exlax/Correctol, are the common over-the-counter laxatives that many people take for mild constipation. Gastroenterologists and knowledgable physicians warn against these products, however, because they are relatively habit forming. It is noted that while the causes of constipation are many, in most people the cause is unknown. Because constipation is a recurring problem, most people take phenolphthalein products recurrently.
Chronic use of phenolphthalein may result in "cathartic colon", a well-accepted entity hallmarked by a dilated, weak colon which is unable to contract normally and thus unable to empty stool, resulting in a vicious cycle. Some studies have shown that in laxative abusers the colon loses its neural control because of damage to the myenteric plexus, possibly due to phenolphthalein effects. Approximately 15% of the phenolphthalein is absorbed, and can cause gripping pain or intestinal cramps.
Castor oil is a well-known stimulant cathartic. The active ingredient in castor oil is ricinoleic acid. Castor oil is a very potent cathartic which often causes abdominal cramping and severe diarrhea. Most patients complain about the taste and the abdominal pain induced by castor oil. Dulcolax (bisacodyl) is a very effective stimulant laxative which is available in tablet or suppository form. Minimal amounts of bisacodyl are absorbed.
Stool softeners, also known as emollients are epitomized by Colace (dioctyl sodium sulfosuccinate), an agent which may be purchased over the counter to soften stools. Most gastroenterologists do not prescribe these compounds because they are relatively ineffective, particularly in the patients with more than mild constipation. The bulking agents are generally preferred to the softening agents.
Mineral oil is also in the group of softeners but has toxicities such as interference with absorption of essential fatty acids and the well-known possibility of aspiration and lipid pneumonitis. Thus most physicians do not prescribe mineral oil.
The present invention contemplates the administration of monosaccharides, and in particular, L-sugars, as laxatives with considerable advantages relative to the previously discussed classes of laxatives, all of which have various undesirable side effects as described above. Specifically, L-sugars are sweet tasting, vary in caloric content, and can readily be combined with other foodstuffs. The first scientifically designed study of the sweetness of L-sugars appears to be that of R. S. Shallenberger, T. E. Acree and C. Y. Lee, Nature 221: 555 (1969), who compared the relative sweetness of the D- and L-enantiomorphs of several sugars, including L-glucose, L-mannose, and L-galactose. Although differences between the enantiomers were observed, their results showed that the sweetness of the D- and L-enantiomers were comparable. Levin in U.S. Pat. No. 4,262,032 suggested employing L-sugars in sweetened edible formulations where the sweetener is non-calorific and less susceptible to spoilage through growth of microorganisms. This reference implied that none of the L-sugars would be metabolized by humans, and also that none will be physiologically or toxicologically detrimental without presenting data which speak to either point. L-sugars have several unique attributes not expected in view of the prior art. In the present invention, we have discovered that, while L-sugars are generally poorly metabolized, there are distinct differences in their excretion patterns and metabolic fates.
L-sugars can act as osmotic laxatives similar to lactulose, but the L-sugar can be formulated and administered in a more convenient and palatable form, such as a candy bar. Lactulose, for example, is available only as a liquid. The L-sugar produces less gas than lactulose, but can produce a lactulose-like effect The L-sugar would be considered "more natural" than lactulose and the onset of action more rapid. L-sugars are poorly absorbed in the human body, and therefore, have an advantage over mannitol, mannose and magnesium citrate in that there is little or no diuretic effect as found when using mannose or mannitol and no danger of magnesium exposure from use of magnesium citrate.
Barium enema prep kits use Dulcolax (bisacodyl) and enemas or the Colyte-type formulas to cleanse the bowel before barium X-rays. An appropriate larger dose of L-glucose may be capable of producing a "cleansing" of the bowel. The convenience and palatability of L-sugars would make them superior to bisacodyl and more palatable than drinking four liters of a high salt liquid over the course of 3-4 hours, e.g., Colyte. In circumstances where gas formation was a minor problem with an L-sugar, then a combination of L-sugar and a smaller (1-2 liter) volume of the polyethylene glycol solution may be advantageous for colon cleansing before X-ray studies, surgery and colonoscopy.
L-sugars have several advantages over the bulking agents currently in use. They can be prepared in a more palatable foodstuff than such products as Perdiem, with its peculiar granular consistency, and Metamucil, with its mucilagenous consistency. L-sugars also would have increased effectiveness and convenience (e.g., as a candy bar) over the prior-utilized products.
In using L-sugars rather than a stimulant agent, patients would avoid the potential harmful effects of recurrent exposure to phenolphthalein. L-sugars allow for more palatable forms of the laxative created in comparison with Exlax and castor oil, and avoids the cramping associated with castor oil and bisacodyl.
L-sugars are more advantageous than the stool softeners currently in use in that they have no sodium or calcium content than, e.g. the Colace and Surfak preparations, respectively.